Lysosomal storage disorders are caused by a defect in lysosomal function that results in accumulation of substances within the lysosome of cells. This defect is usually a consequence of deficiency of a single enzyme required for the metabolism of lipid, glycogen, glycoprotein, or mucopolysaccharide. Gaucher disease, the most common lysosomal storage disorder, is caused by a deficiency in β-glucocerebrosidase (also known as beta-glucosidase or GCase).
Gaucher disease is an autosomal recessive disorder caused by mutations in the GBA gene, which encodes for GCase. This enzyme functions inside the acidic environment of the lysosome and reacts with two key substrates: glucocerebroside (GlcCer) and Glucosylsphingosine (GlcSph). Mutations in the GBA gene lead to a partial or total loss of function phenotype, and can be characterized by reduced or absent GCase activity in the lysosome, and accumulation of GCase substrate, leading to a variety of symptoms.
Gaucher disease is categorized into three types. Approximately 95% of patients with Gaucher exhibit Type 1, where onset occurs at childhood or adulthood and has been described as non-neuronopathic. Type 2 is characterized by the presence of neurologic involvement during childhood, whereas neurologic involvement presents during adolescence or adulthood in Type 3 Gaucher disease.
Parkinson's disease is an adult neurodegenerative disorder that is characterized by a progressive loss of motor and other neural functions. The disease can be identified pathologically by two primary features: neuronal death and Lewy bodies. As the disease progresses, the neurons in the brain that control movement begin to die and the hallmark clinical signs of Parkinson's begin to appear, including tremors, stiffness, and difficulty with posture. Within the remaining surviving neurons, proteins and lipids begin to accumulate into bodies known as Lewy bodies. One key component identified within Lewy bodies is alpha-synuclein, and variations in its gene, SNCA, are associated with inherited and sporadic Parkinson's.
Accordingly, there is a need for additional treatments for lysosomal storage disorders such as Gaucher disease and degenerative disorders of the central nervous system such as Parkinson's disease.